The broad, long-term objective of this proposal is to develop a safe, effective, and widely applicable immunotherapy of myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) using the transfusion of lymphocytes from allogeneic donors. Allogeneic blood or marrow transplantation, or alloBMT, is a potentially curative therapy of MDS and CMML, but the morbidity and mortality of the procedure precludes its use in this elderly population of patients, most of whom lack HLA-identical donors. Recent pre-clinical data demonstrate that significant disease responses can be obtained with minimal toxicity by treating tumor-bearing animals with cyclophosphamide (Cy) followed by an infusion of CD8+ T cell- depleted lymphocytes from histoincompatible donors. In contrast to unmanipulated donor lymphocyte infusions (DLI), which engrafted durably and caused lethal acute graft-versus-host disease (GVHD), the CD8+ T cell-depleted DLI engrafted only transiently and did not cause GVHD or aplasia. Potential mechanisms of the anti-tumor effect of Cy followed by CD8+ T cell-depleted DLI include a transient graft-versus-tumor reaction from donor CD4+ T cells or NK cells, or an awakening of a dormant anti-tumor immune response among host CD8+ T cells. Based upon these results, the central specific aim of the proposal is to conduct a clinical trial to determine the maximally tolerated dose and anti-tumor efficacy of partially HLA-mismatched (haploidentical), CD8+ T cell-depleted peripheral blood cells (PBCs) given after Cy to patients with MDS or CMML. The investigational product to be tested, CD8+ T cell depleted PBMCs, will be derived from peripheral blood collections using the CliniMACS System with CliniMACS CDS Reagent (Miltenyi Biotec, Auburn, CA). A secondary aim of the proposal will be to characterize the effects of therapy on the host CD8+ T cell repertoire. Relevance of the research to public health: White blood cell transfusions from healthy donors can be an effective cancer treatment because immune cells in the transfusion are capable of recognizing and attacking cancer cells. Unfortunately, some of the cells, called CD8+ T cells, can destroy normal tissues as well. We wish to test whether removal of these CD8+ T cells enhances the safety of WBC transfusions for patients with blood cancers. [unreadable] [unreadable] [unreadable]